Abstract Number: PB0334
Meeting: ISTH 2022 Congress
Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » Inherited Thrombocytopenias
Background: Patients with MYH9-related disorders (MYH9-RD) show a strong genotype-phenotype correlation based on thrombocytopenia, renal disease, deafness and/or cataracts. Beyond platelets, the cellular effects, and underlying biochemical mechanism, of MYH9 variants which affect to the heavy chain of non-muscle myosin IIA (NMMHCII-A) are poorly characterized. Recurrent infections have not been previously described.
Aims: To characterize the biochemical and dynamic behavior of the MYH9 variant c.3486G>C [p.R1162S] and assess its correlation with alterations observed in leukocytes and recurrent infections.
Methods: MYH9-RD was diagnosed in five patients from the same family with recurrent infections since early age (Table 1). The behavior of neutrophils, activated T cells and monocyte-derived dendritic cells was examined in adhesion and migration assays. NMMHCII-A 1162S mutant was expressed as GFP-coupled protein in a Myh9-deficient cell line for cellular and biochemical characterization.
Results: Leukocyte anomalies consisted of morphology and migratory defects in neutrophils, T lymphoblast and monocyte-derived dendritic cells (mDCs). Upon adhesion to fibronectin, neutrophils showed striking, highly-organized and stack-like NMMHCII-A structures consistent with increased filament stability (Fig.1A). Neutrophils bearing this variant also showed decreased fMLP-dependent migration through Boyden chambers (Fig.1B). T lymphoblasts adhered to fibronectin displayed increased polarization and spreading area (Fig.1C) whereas the adhesion capability of mDCs was impaired (Fig.1D). Further analysis of the migratory ability of mDCs on 3D substrates showed an aberrant CCL19-dependent migration in collagen gels (Fig.1E). Surprisingly, mDCs carrying this variant displayed decreased cellular coherence and increased release of cytoplastic fragments when navigating through collagen fibers (Fig.1F). Expression of GFP-NMMHCIIA R1162S in a MYH9-deficient cell line revealed assembly into abnormally stable mini-filaments dynamically distinct from wild type filaments (Fig.1G).
Conclusion(s): The MYH9 variant p.R1162S led to specific perturbations of the biochemical interactions and dynamics of mutant NMMHCII-A protein. The leukocyte alterations reported here could underlie the recurrent infections observed in patients carrying this variant.
To cite this abstract in AMA style:
Llorente-González C, Millán-Salanova M, Marin-Quilez A, Díaz-Ajenjo L, Santos-Mínguez S, Miguel-García C, Benito R, González-Porras J, Rivera J, Vicente-Manzanares M, Bastida J. A novel R1162S variant in MYH9 alters the biochemical interactions and dynamics of NMMHC-IIA, induces severe macrothrombocytopenia and perturbs leukocyte function and cellular coherence [abstract]. https://abstracts.isth.org/abstract/a-novel-r1162s-variant-in-myh9-alters-the-biochemical-interactions-and-dynamics-of-nmmhc-iia-induces-severe-macrothrombocytopenia-and-perturbs-leukocyte-function-and-cellular-coherence/. Accessed March 21, 2024.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/a-novel-r1162s-variant-in-myh9-alters-the-biochemical-interactions-and-dynamics-of-nmmhc-iia-induces-severe-macrothrombocytopenia-and-perturbs-leukocyte-function-and-cellular-coherence/